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09.11.2017 | Original Article | Ausgabe 3/2018 Open Access

Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice

Zeitschrift:: Brain Structure and Function > Ausgabe 3/2018

Autoren:: Martin Regensburger, Sebastian R. Schreglmann, Svenja Stoll, Edward Rockenstein, Sandra Loskarn, Wei Xiang, Eliezer Masliah, Beate Winner

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The online version of this article (https://doi.org/10.1007/s00429-017-1561-5) contains supplementary material, which is available to authorized users.

Abstract

In the adult mammalian hippocampus, new neurons are constantly added to the dentate gyrus. Adult neurogenesis is impaired in several neurodegenerative mouse models including α-synuclein (a-syn) transgenic mice. Among different a-syn species, a-syn oligomers were reported to be the most toxic species for neurons. Here, we studied the impact of wild-type vs. oligomer-prone a-syn on neurogenesis. We compared the wild-type a-syn transgenic mouse model (Thy1-WTS) to its equivalent transgenic for oligomer-prone E57K-mutant a-syn (Thy1-E57K). Transgenic a-syn was highly expressed within the hippocampus of both models, but was not present within adult neural stem cells and neuroblasts. Proliferation and survival of newly generated neurons were unchanged in both transgenic models. Thy1-WTS showed a minor integration deficit regarding mushroom spine density of newborn neurons, whereas Thy1-E57K exhibited a severe reduction of all spines. We conclude that cell-extrinsic a-syn impairs mushroom spine formation of adult newborn neurons and that oligomer-prone a-syn exacerbates this integration deficit. Moreover, our data suggest that a-syn reduces the survival of newborn neurons by a cell-intrinsic mechanism during the early neuroblast development. The finding of increased spine pathology in Thy1-E57K is a new pathogenic function of oligomeric a-syn and precedes overt neurodegeneration. Thus, it may constitute a readout for therapeutic approaches.

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Supplementary material 1 Supplemental Fig. 1 Direct spatial relation of transgenic a-syn and newborn neuron dendrites and spines. Immunohistochemical localization of WTS (A) and E57K (B) a-syn in the molecular layer of transgenic mice 1 month after GFP-labeling of newborn neurons. In both groups, transgenic a-syn is found at high levels in the molecular layer and in the hilus, in direct proximity to the dendrites of GFP-positive newborn neurons, including thin spines and mushroom spines (labeled by intersecting bars). Scale bars overview 10 µm, insets 2 µm (TIFF 9011 kb)

429_2017_1561_MOESM1_ESM.tif

Supplementary material 2 Supplemental Fig. 2 Subpopulations of neuroblasts in a-syn transgenic mice. (A) Low magnification overview of doublecortin (DCX) staining of the dentate gyrus. (B–D) Sample images of DCX-positive cells with early, intermediate, and late-stage morphology, respectively. (E–H) DCX-positive cells in Thy1-WTS animals. The total number of DCX-positive cells was unchanged (E; compare Fig. 3c). The subpopulations of early (F) and intermediate (G) neuroblasts were unchanged in Thy1-WTS. There was a significant reduction of late-stage neuroblasts when compared to NTG (H). (I–L) Quantification of DCX-positive cells in Thy1-E57K animals. Similar to Thy1-WTS, there were no significant changes in the total number of neuroblasts (I, compare Fig. 3g) as well as the subpopulations of early (J) and intermediate (K) neuroblasts. In Thy1-E57K, there was no change in the number of the late-stage neuroblasts (L). Scale bars (A) 200 µm, (B–D) 20 µm. * P < 0.05 (TIFF 1354 kb)

Supplementary material 3 Supplemental Fig. 3 Hippocampal cell death and number of neurons at 4 months of age. (A) Representative micrograph of aCaspase3+ cells in the granule cell layer. (B) Representative overview image of NeuN+ cells in the hippocampus. GCL granule cell layer. (C–H) Quantification of aCaspase3+ cells, NeuN+ cells, and volume in the granule cell layer and the CA3 region. No significant differences were observed between the groups. Scale bars (A) 20 µm, (B) 500 µm (TIFF 1370 kb)

429_2017_1561_MOESM3_ESM.tif

Supplementary material 4 (DOCX 115 kb)

429_2017_1561_MOESM4_ESM.docx

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Titel: Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice
Autoren:: Martin Regensburger
Sebastian R. Schreglmann
Svenja Stoll
Edward Rockenstein
Sandra Loskarn
Wei Xiang
Eliezer Masliah
Beate Winner
Publikationsdatum: 09.11.2017
DOI: https://doi.org/10.1007/s00429-017-1561-5
Verlag: Springer Berlin Heidelberg
Zeitschrift: Brain Structure and Function
Ausgabe 3/2018
Print ISSN: 1863-2653
Elektronische ISSN: 1863-2661

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Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice

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